The authors have declared that no competing interests exist.
Conceived and designed the experiments: DCJ CC MM AM AA AM DJJ APK CCK CvdH MCH. Performed the experiments: DCJ CC MM AM AA AM DJJ APK CCK CvdH MCH. Analyzed the data: DCJ CC MM AM AA AM DJJ APK CCK CvdH MCH. Contributed reagents/materials/analysis tools: DCJ CC MM AM AA AM DJJ APK CCK CvdH MCH. Wrote the paper: DCJ CC MM AM AA AM DJJ APK CCK CvdH MCH.
The Malawian government recently changed its prevention of mother-to-child transmission (PMTCT) regimen and plans to change its first-line antiretroviral therapy (ART) regimen to Tenofovir(TDF)/Lamivudine/Efavirenz as a fixed-dose combination tablet. Implementation could be challenging if baseline creatinine clearance (CrCl) screening were required to assess renal function prior to TDF therapy. Our goal is to determine predictors of CrCl<50 ml/min among HIV-infected, ART-naïve individuals.
Data on HIV-infected, ART-naïve adults screened for enrollment into 5 HIV clinical trials in Lilongwe, Malawi were combined for a pooled analysis of predictors for CrCl<50 ml/min. CrCl was derived from the Cockroft-Gault equation. Multivariable logistic regression modeled the association of age, body mass index (BMI), hemoglobin, CD4 cell count <350 cells/mm3, gender, and pregnancy with CrCl<50 ml/min.
The analysis included 3508 patients with values for creatinine clearance. Most subjects were female (90.6%) with a median age of 26 years (IQR 22–29). The median CD4 cell count was 444 (IQR 298.0–561.0), and 85.2% percent of women in our study were pregnant. Few patients had CrCl<50 ml/min (n = 38, 1.1%). A BMI less than 18.5 in non-pregnant females (OR = 8.87, 95% CI = 2.45–32.09)) was associated with CrCl<50 ml/min. Hemoglobin level higher than 10 g/dL in males (OR = 0.69, 95% CI = 0.56–0.86) and non-pregnant females (OR = 0.21, 95% CI = 0.04–0.97) was protective against CrCl<50 ml/min.
Our findings indicate few patients would be excluded from a TDF-based antiretroviral regimen, suggesting baseline creatinine clearance assessment may not be necessary for implementation. However, in ART settings individuals with low BMI or anemia could potentially be at increased risk for lower CrCl.
Malawi has one of the highest HIV prevalence rates in the world. National HIV adult prevalence in Malawi reached a high of 26% in 1998 and has since decreased to about 12% in 2010
Malawi's current first-line antiretroviral therapy and former prevention of mother-to-child transmission (PMTCT) regimen consists of stavudine, lamivudine and nevirapine. Stavudine has long-term side-effects such as lactic acidosis, hepatic steatosis and lipo-atrophy
A creatinine clearance (CrCl) rate ≥50 ml/min is recommended before starting TDF for efficient renal clearance
All involved studies were approved by the National Health Sciences Research Committee, the University of North Carolina Ethics Committee. The BAN study was also approved by CDC ethics committee. All subjects provided written informed consent for the participation in the specified clinical trial that included data collected from screening onward.
This cross-sectional study combines data on 3508 HIV-infected, ART-naïve adults screened for enrollment to five HIV clinical trials conducted in Lilongwe, Malawi from 04/08/2004 to 07/26/2009: 625 screened for the HIV Prevention Trial Network 052 (HPTN 052: ClinicalTrials.gov Identifier NCT0007458); 268 for the AIDS Clinical Trial Group (ACTG) A5175 (ClinicalTrials.gov Identifier NCT00096824), A5208 (ClinicalTrials.gov Identifier NCT00089505), A5221 (ClinicalTrials.gov Identifier NCT00108862); and 2615 for the Breastfeeding, Antiretroviral, and Nutrition Study (BAN: ClinicalTrials.gov Identifier NCT00164736)
The outcome for this analysis was CrCl<50 ml/min based on dichotomization of CrCl calculated from the Cockroft-Gault equation (CG): Creatinine clearance = [(140-age)*(weight in Kg)*(0.85 if female)]/(72*Creatinine mg/dL)
Bivariate analyses were used to assess the crude association for each covariate with CrCl<50 ml/min according to both CrCl equations. Differences in categorical variables were assessed using the χ2-square test, while differences in means were assessed using the student's t test and Wilcoxon rank-sum test. Descriptive characteristics were stratified by pregnancy status due to the large amount of pregnant women in our study. Analysis of variance was used to assess the homogeneity of each covariate across each clinical trial. Multivariable logistic regression using SAS 9.2 assessed risk factors associated with CrCl<50 ml/min, while adjusting or stratifying on screening population. A sensitivity analysis assessing CrCl of <90 ml/min in pregnant women was conducted to assess the robustness of CrCl in pregnant women in our models.
Most study subjects were female (90.6%) with a median age of 26 years (IQR 22–29). The median CD4 cell count was 444 cells/mm3 (IQR 298.0–561.0). The median weight of our study participants (57 kg (IQR 52–63)) is comparable to a study of 4 ART clinics where the median weight of individuals seeking ARVs was 55 kg (IQR 49–63)
BAN n = 2615 | Combined ACTG n = 268 | HPTN052 n = 625 | ||||
Not Pregnant (N = N/A) | Pregnant (N = 2615) | Not Pregnant (N = 204) | Pregnant (N = 14) | Not Pregnant (N = 550) | Pregnant (N = 75) | |
Age | ||||||
Mean (SD) | N/A | 24.7 (4.5) | 22.9 (13.4) | 31.2 (5.7) | 34.4 (9.9) | 26.7 (5.4) |
Median (IQR) | N/A | 24.0 (21.1–27.0) | 20.0 (15.0–26.0) | 30.0 (28.0–34.0) | 33.0 (27.0–40.0) | 26.0 (22.0–30.0) |
Gender | ||||||
Female | N/A | 2615 (100.0) | 188 (74.0) | 14 (100.0) | 280 (50.9) | 75 (100.0) |
Male | N/A | N/A | 66 (26.0) | N/A | 270 (49.1) | N/A |
BMI (kg/m2) | ||||||
Mean (SD) | N/A | 24.1 (2.9) | 21.3 (3.4) | 21.5 (3.6) | 21.9 (3.3) | 23.6 (3.1) |
Median (IQR) | N/A | 23.7 (22.2–25.6) | 20.7 (19.1–22.0) | 20.9 (19.4–22.6) | 21.2 (19.6–23.5) | 22.9 (21.0–24.9) |
BMI (kg/m2) | ||||||
<18.5 | N/A | 844 (32.3) | 49 (19.3) | 2 (14.3) | 75 (13.6) | 5 (6.7) |
≥18.5 | N/A | 1771 (67.7) | 205 (80.7) | 12 (85.7) | 475 (86.4) | 70 (93.3) |
Hemoglobin (g/dL) | ||||||
<10 | N/A | 622 (23.8) | 45 (17.8) | 2 (14.3) | 43 (7.9) | 13 (17.3) |
≥10 | N/A | 1993 (76.2) | 208 (82.2) | 12 (85.7) | 500 (92.1) | 62 (82.7) |
Hemoglobin (g/dL) | ||||||
Mean (SD) | N/A | 10.8 (1.2) | 11.4 (2.2) | 12.3 (1.6) | 12.8 (2.1) | 11.2 (1.9) |
Median (IQR) | N/A | 10.8 (10.0–11.7) | 11.6 (10.4–12.9) | 12.6 (11.2–13.5) | 12.8 (11.4–14.3) | 11.4 (10.3–12.2) |
CD4+ T-cell count (cells/mm3) | ||||||
Mean (SD) | N/A | 482.7 (198.2) | 255.6 (195.5) | 330.6 (175.2) | 365.2 (233.9) | 372.5 (183.6) |
Median (IQR) | N/A | 441.0 (334.0–585.0) | 212.5 (121.0–339.0) | 288.5 (237.0–422.0) | 324.5 (206.0–502.0) | 355.5 (219.0–490.0) |
CD4+ T-cell count (cells/mm3) | ||||||
>350 | N/A | 1838 (70.3) | 196 (77.2) | 8 (57.1) | 297 (54.0) | 36 (48.0) |
≤350 | N/A | 777 (29.7) | 58 (22.8) | 6 (42.9) | 253 (46.0) | 39 (52.0) |
ALT (U/L) | ||||||
Mean (SD) | N/A | 14.1 (5.8) | 22.9 (13.4) | 244.1 (68.2) | 23.7 (13.4) | 14.6 (5.0) |
Median (IQR) | N/A | 13.0 (11.0–16.0) | 20.0 (15.0–26.0) | 235.0 (201.0–289.0) | 20.0 (15.0–27.0) | 14.0 (12.0–17.0) |
Creatinine Clearance <50 ml/min | ||||||
Yes | N/A | 9 (0.3) | 9 (3.5) | 1 (7.1) | 19 (3.5) | 0 (0.0) |
No | N/A | 2606 (99.7) | 245 (96.5) | 13 (92.9) | 531 (96.5) | 75 (100.0) |
Creatinine Clearance in Pregnant Females <90 ml/min | ||||||
Yes | N/A | 410 (15.7) | N/A | 11 (78.6) | N/A | 8 (10.7) |
No | N/A | 2205 (84.3) | N/A | 8 (21.4) | N/A | 67 (89.3) |
Few patients had CrCl<50 ml/min by the CG equation (n = 38, 1.1%). The proportion with CrCl<50 ml/min differed by study population (
|
|
|
||||
Crude OR (95% CI) | Adjusted OR (95% CI) | Crude OR (95% CI) | Adjusted OR (95% CI) | Crude OR (95% CI) | Adjusted OR (95% CI) | |
Age (per year increase) | 1.15 (1.03–1.27) | 1.14 (1.03, 1.28) | 1.07 (0.98–1.16) | 1.07 (0.98, 1.16) | 1.10 (1.06–1.15) | 1.13 (1.07, 1.19) |
Gender | ||||||
Female | N/A | N/A | 1.32 (0.33–5.28) | 1.75 (0.34, 9.07) | 2.94 (1.10–7.84) | 1.19 (0.35, 4.07) |
Male | N/A | N/A | Ref | Ref | Ref | Ref |
BMI (kg/m2) | ||||||
<18.5 | 1.68 (0.45–6.28) | 1.68 (0.44, 6.30) | 4.61 (1.28–16.58) | 4.27 (1.07, 17.11) | 5.40 (2.10–13.86) | 5.23 (1.77, 15.45) |
≥18.5 | Ref | Ref | Ref | Ref | Ref | Ref |
Hemoglobin (per g/dL increase) | ||||||
≥10 | 1.09 (0.23, 5.27) | 1.10 (0.22, 5.43) | 0.30 (0.8, 1.11) | 0.34 (0.08, 1.38) | 0.12 (0.5, 0.31) | 0.07 (0.02, 0.23) |
<10 | Ref | Ref | Ref | Ref | Ref | Ref |
CD4+ T-cell count (cells/mm3) | ||||||
>350 | 1.48 (0.31–7.14) | 1.53 (0.31, 7.51) | 0.34 (0.04–2.77) | 0.44 (0.05, 3.74) | 0.52 (0.19–1.38) | 0.84 (0.27, 2.67) |
≤350 | Ref | Ref | Ref | Ref | Ref | Ref |
Currently Pregnant |
||||||
No | N/A | N/A | 0.48 (0.06, 4.06) | 0.42 (0.04, 4.58) | N/A | N/A |
Yes | N/A | N/A | Ref | N/A | N/A | N/A |
Models adjusted for age, gender, BMI, hemoglobin, CD4, and pregnancy.
No pregnant women in the HTPN 052 clinical trial experienced creatinine clearance <50 mg/dl. All women screened for the BAN clinical trial were pregnant.
|
|
|
||||
Crude OR (95% CI) | Adjusted OR (95% CI) | Crude OR (95% CI) | Adjusted OR (95% CI) | Crude OR (95% CI) | Adjusted OR (95% CI) | |
Age (per year increase) | 1.07 (1.02, 1.12) | 1.08 (1.02, 1.14) | 1.12 (1.06, 1.18) | 1.17 (1.08, 1.26) | 1.14 (1.04, 1.27) | 1.15 (1.04, 1.27) |
BMI (Kg/m2) | ||||||
<18.5 | 2.68 (0.94, 7.67) | 1.67 (0.52, 5.38) | 7.63 (2.39, 24.67) | 8.87 (2.45, 32.09) | 2.18 (0.63, 7.57) | 2.26 (0.65, 7.86) |
≥18.5 | Ref | Ref | Ref | Ref | Ref | Ref |
CD4+ T-cell count | ||||||
>350 cells/mm3 | 0.49 (0.13, 1.77) | 0.78 (0.19, 3.20) | 0.62 (0.18, 2.08) | 0.73 (0.16, 3.44) | 1.02 (0.26, 3.94) | 1.04 (0.26, 4.11) |
≤350 cells/mm3 | Ref | Ref | Ref | Ref | Ref | Ref |
Hemoglobin (per g/dL increase) | ||||||
≥10 | 0.10 (0.04, 0.29) | 0.69 (0.56, 0.86) | 0.23 (0.07, 0.80) | 0.21 (0.04, 0.97) | 1.23 (0.26, 5.82) | 1.34 (0.28, 6.48) |
<10 | Ref | Ref | Ref | Ref | Ref | Ref |
Models adjusted for Age, BMI, CD4 cell count, and hemoglobin.
BAN (N = 2615) |
Combined ACTG (N = 14) | HTPN 052 (N = 75) | ||||
Crude OR (95% CI) | Adjusted OR (95% CI) | Crude OR (95% CI) | Adjusted OR (95% CI) | Crude OR (95% CI) | Adjusted OR (95% CI) | |
Age (per year increase) | 1.12 (1.09, 1.14) | 1.12 (1.09, 1.14) | 1.78 (0.91, 3.50) | 1.07 (1.02, 1.13) | 1.10 (0.96, 1.26) | 1.10 (1.08, 1.12) |
BMI (kg/m2) | ||||||
<18.5 | 1.19 (0.95, 1.49) | 1.20 (0.96, 1.51) | 1.20 (0.85, 1.72) | 1.31 (1.18, 1.45) | 2.25 (0.22, 23.0) | 6.70 (3.34, 13.41) |
≥18.5 | Ref | Ref | Ref | Ref | Ref | Ref |
Hemoglobin (per g/dL increase) | ||||||
≥10 | 0.63 (0.49, 0.79) | 0.65 (0.51, 0.83) | 0.71 (0.28, 1.81) | 0.67 (0.30, 1.49) | 1.02 (0.70, 1.50) | 1.44 (0.76, 2.69) |
<10 | Ref | Ref | Ref | Ref | Ref | Ref |
CD4+ T-cell count (cells/mm3) | ||||||
>350 | 1.38 (1.11, 1.72) | 1.32 (1.06, 1.67) | 1.67 (0.12, 24.25) | 1.19 (0.60, 2.39) | 3.09 (0.58, 16.42) | 1.01 (0.71, 1.45) |
≤350 | Ref | Ref | Ref | Ref | Ref | Ref |
Models adjusted for age, BMI, hemoglobin, CD4 cell count.
All women screened for the BAN clinical trial were pregnant.
CrCl<50 ml/min was associated with BMI and hemoglobin level. A BMI ≤18.5 kg/m2 was significantly associated with increased odds for CrCl<50 ml/min in both the HPTN 052 and combined ACTG trials in univariate analysis (HPTN 052: OR = 5.40, 95% CI = 2.10–13.86, p-value≤0.001; ACTG: OR = 4.61, 95% CI = 1.28–16.58, p-value≤0.05;
Sensitivity analyses assessed factors associated with CrCl<90 ml/min in pregnant individuals by clinical trial while adjusting for age, BMI, hemoglobin, and CD4 cell count was similar to our main models. Covariates in our sensitivity analysis that differed from our main models varied according to clinical trial. Being underweight was associated with CrCl<90 ml/min in the combined ACTG trials (OR = 1.31 95%CI 1.18–1.45), but not associated with CrCl<50 ml/min in the combined ACTG trials of our main models. Hemoglobin values greater than 10 g/dL was protective against a CrCl<90 ml/min in the BAN trials (OR = 0.65 95%CI = 0.51–0.83), but only significantly associated with CrCl<50 ml/min in the HPTN052 trial of our main models. CD4 cell count was found to be protective against CrCl<90 ml/min in the BAN trials (OR = 1.31 95%CI 1.18–1.45), but not associated with CrCl<50 ml/min in any trial of our main models (
Among 3508 HIV-infected, ART-naïve adults screened for enrollment to five HIV clinical trials conducted in Lilongwe, Malawi, we found that CrCl<50 ml/min was rare, suggesting that few patients would be excluded from receiving the public provision of TDF-based antiretroviral regimen based on this criteria. The small proportion of patients with low CrCl is comparable to other studies assessing CrCl in HIV positive individuals in populations similar to ours
Many indicators suggest our population is comparable to other HIV-infected, ART-naïve cohorts within Malawi. Studies conducted in the PMTCT populations of Thyolo District Hospital located in rural Malawi have shown the median age of PMTCT study participants is 22 years, making our study sample of comparable age to other Malawian PMTCT cohorts
Our cohort's median CD4 cell count, at 444 cells/ml, is higher than most studies assessing risk factors associated with low creatinine clearance in HIV-infected individuals
Our study's association between low BMI and CrCl<50 ml/min agrees with the current literature on renal insufficiency among HIV-infected, ART-naïve individuals. A cross-sectional survey of 2588 individuals assessing creatinine clearance in HIV-infected patients in France found that a BMI<22 kg/m2 was associated with both mild and advanced renal insufficiency
Low hemoglobin values are associated with renal insufficiency in people living with HIV. Time to death due to end-stage renal disease in individuals living with HIV is significantly shorter for those with low hemoglobin values compared to normal values
Our findings show increases in hemoglobin and BMI have significant protective affects against CrCl<50 ml/min is consistent with other literature. HIV/AIDS-associated nephropathy (HIVAN) is associated with low hemoglobin levels
Models stratified by pregnancy show only increases in age to be a significant factor associated with CrCl<50 mg/dl in ART-naïve pregnant individuals, while lower BMI and hemoglobin are associated with a increased likelihood of CrCl<50 mg/dl for non-pregnant individuals. The lack of significant factors associated with CrCl<50 mg/dl and pregnancy could possibly be due to the renal changes that occur during pregnancy
While CD4 cell count was not significant in our multivariate models, 20 of the 38 individuals with CrCl<50 ml/min using the CG equation also had CD4 counts less than 200 cells/mm3 (52.6%). Of the 38 individuals, 11 had a BMI under 18.5 (28.9%), and 7 of these also had a hemoglobin <11 g/dl and CD4 <200 cells/mm3. This suggests that when clinically assessing patients for potential CrCl<50 ml/min in a general clinical setting, a disproportionate number of afflicted individuals (18.4%) will have low hemoglobin, BMI, and CD4 cell counts. While we were not able to develop a clinical algorithm for assessing CrCl<50 ml/min due to small numbers of clients with this outcome, developing and validating such an algorithm prospectively with a larger study sample could be possible.
There are some limitations to our study. We recognize that the CG equation does not addresses renal tubular function as can be assessed by evaluating proteinuria through dipstick, urine protein∶creatinine ratio, or fractional excretion of phosphate. The clinical trials included in this pooled analysis were all conducted in the urban city of Lilongwe and may not be representative of all the PMTCT and ART populations in Malawi. A recent WHO report suggests that only 17% of Malawi's population live in urban areas
Enrollment criteria for the respective trials varied, and if CD4 clinic data were available and it precluded patients from the study, they would not have been referred for trial screening. The ACTG 5221 and ACTG 5208 trials did not screen individuals with known high CD4 counts, and the BAN study did not enroll individuals with known CD4<250 cells/µL. Therefore, the pooled population may have oversampled sicker individuals for the ACTG screening population and healthier individuals for the BAN screening population. Such misrepresentation is expected to be minimal as individuals presenting for ART tend to be sicker on average and those presenting for PMTCT tend to be healthier. However, it is possible patients screened for the five clinical trials may not be representative of a routine clinic setting because screened individuals might be healthier than normal.
The majority of our population consists of pregnant women screened through the BAN study. This could potentially create an underrepresentation of HIV-infected, ART-naïve men. However, a main goal of our study is to focus on predictive factors of potential renal failure for pregnant mothers in a PMTCT program. Additionally, regardless of the gender imbalance across studies, the data used in this pooled analysis is, to our knowledge, the only data containing serum creatinine values of HIV-infected, ART-naïve individuals in Malawi. It is possible the CG equation could misrepresent creatinine clearance in our study because the majority of our population is pregnant and the equation requires the weight and gender of each subject. To address this potential limitation, we included a sensitivity analysis using CrCl<90 ml/min in pregnant individuals as an outcome.
Our study suggests that few eligible HIV-infected Malawians would be excluded from a TDF-based ART regimen. Limited resources for measuring serum creatinine should be directed towards individuals with low values for BMI or hemoglobin and who are not pregnant, since these individuals are at the greatest risk for a CrCl<50 ml/m.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.